Hydrogen Peroxide → N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine

HRID 861120Notes

Reaction equation

HRID 861120 reaction equation
COB1C2CC[CH2:11][CH:4]1[CH2:5]CC2.C([Mg]Br)(C)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[C:48]([NH:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:47]=3)=[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([NH:40][CH2:41][CH2:42][CH2:43][CH3:44])[N:34]3[N:33]=2)=[CH:28][CH:27]=1.[OH-].[Na+].OO>O1CCCC1.O.CCOCC.CN(C)C=O>[CH2:41]([NH:40][C:39]1[N:34]2[N:33]=[C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:4]([CH3:11])=[CH2:5])=[CH:27][CH:28]=3)[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[C:48]([NH:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:47]=3)=[C:35]2[CH:36]=[CH:37][CH:38]=1)[CH2:42][CH2:43][CH3:44]

Participants

11

Reactant 6

HCID 784Hydrogen PeroxideHCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 5449649-Methoxy-9-borabicyclo(3.3.1)nonaneHCID 102068202-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amineHCID 178456138HCID 178456138, compound

Product 1

HCID 10204515N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amineYield 27.5%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane (1 mL, 1.0 M in hexane, 1.0 mmol) in tetrahydrofuran (5 mL) was added isopropenylmagnesium bromide (2.0 mL, 0.5 M in tetrahydrofuran, 1.0 mmol) dropwise. The resultant solution was stirred at −78° C. for 5 minutes, then allowed to warm to room temperature. After 1 hour, potassium phosphate (0.33 mL, 3 M aqueous, 1.0 mmol) was added followed by N,N-dimethylformamide (5 mL), 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.20 mmol), and bis(diphenylphosphinoferrocene)palladium(II) chloride dichloromethane complex (17 mg, 0.02 mmol). The resultant solution was stirred for 72 hours at room temperature. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (6:1 to 4:1 to 2:1 hexanes:ethyl acetate) provided impure product. This material was taken up in tetrahydrofuran, cooled to 0° C. and 1 mL each of 10% aqueous sodium hydroxide and 30% hydrogen peroxide were added. After 30 minutes, the mixture was quenched with saturated aqueous sodium thiosulfate. Aqueous workup as reported above followed by similar chromatography provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine (25 mg, 27%) as an oil. 1H NMR (CDCl3): δ 8.00 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 2 H), 7.54 (d, 2 H), 7.30 (m, 1 H), 6.35 (d, 1 H), 6.07 (m, 1 H), 5.99 (d, 1 H), 5.46 (s, 2 H), 5.22 (broad, 1 H), 5.14 (s,1 H), 3.47 (m, 2 H), 3.36 (m, 2 H), 2.20 (s, 3 H), 1.77–1.42 (m, 8 H), 1.00–0.95 (m 6 H); MS m/z 455 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt.

Workup

  1. washThe organic layer was washed with brine
  2. extractionThe aqueous layer was extracted with ether
  3. dry with materialthe combined organics dried over magnesium sulfate
  4. filtrationFiltration and concentration
  5. customprovided impure product
  6. temperaturecooled to 0° C.
  7. waitAfter 30 minutes
  8. customthe mixture was quenched with saturated aqueous sodium thiosulfate

Sources & evidence

ORD record
ord-d3722e90a11946b68c0c062d2c41a959
Source dataset
uspto-grants-2006_12
Patent number
US07153855B2

Reaction notes

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